The association between air pollution and morbidity and mortality caused by respiratory and cardiovascular diseases is well established; in addition, initial evidence suggests that air pollution may also negatively affect the central nervous system (CNS) and contribute to CNS diseases. Elevated air pollution is associated with decreased cognitive functions and other behavioral alterations, and increased incidence of neurodegenerative disease pathologies. Particulate matter (PM), and in particular ultrafine particulate matter (UFPM; <100 nm), is believed to be the most widespread threat and has been heavily implicated in disease. Traffic-related air pollution is a major contributor to global air pollution, and diesel exhaust (DE) is its most important component, as it is a major constituent of ambient PM, particularly of UFPM. Few studies in animals have shown that exposure to DE may cause neurotoxicity, with the most prominent effects on the CNS being oxidative stress and neuroinflammation. Among factors which can affect neurotoxic outcomes, gender together with age and genetic background, are considered the most relevant. The general aim of this proposal is to investigate the neurotoxicity of DE, by testing the hypothesis that gender difference in susceptibility exist, with male being more sensitive. This hypothesis is based on recent findings in our laboratory on the enzyme paraoxonase 2 (PON2), an intracellular mitochondrial enzyme, expressed in the CNS, with has potent anti-oxidant properties. PON2 levels are higher in females in all brain regions, and this confers some degree of resistance to oxidants. Preliminary findings in mice upon acute DE exposure are supportive of such hypothesis. The project, articulated in four specific aims, proposes to investigate the neurotoxicity of acute and chronic exposure to DE in male and female mice, with the underlying hypothesis of a higher susceptibility of males. Indicators of oxidative stress, cell death, and microglia activation/neuroinflammation will be measured in brain regions and in peripheral tissues; furthermore the hypothesis that DE-induced neuroinflmmatation will inhibit adult neurogenesis will be tested. Additional studies will investigate olfactory functions, motor activit and learning and memory in DE-exposed mice. Finally, primary neurons from olfactory bulb, hippocampus, and striatum neurons from mice of both genders will be exposed to DE-PM either alone or in the presence of microglia and/or astrocytes to investigate cellular mechanisms of DE neurotoxicity and neuroinflammation.